2,4-benzoxazepine derivatives

ABSTRACT

2,4-Benzoxazepine derivatives of formula (I)   wherein R is hydrogen, lower alkyl or benzyl, R&#39;&#39; and R&#39;&#39;&#39;&#39; independently represent hydrogen, phenyl or substituted phenyl, not more than one of which is hydrogen and X is hydrogen, halo or lower alkoxy. The fundamental seven-membered benzoxazepine system is prepared by reacting a compound of formula (II)   wherein R, R&#39;&#39;, R&#39;&#39;&#39;&#39; and X have the above meanings, with phosgene or an equivalent carbonylating agent. The compounds of the invention have hypnotic, sedative and myorelaxing activity.

United States, Patent [191 Fontanella et a].

v June 18, 1974 2,4-BENZOXAZEPINE DERIVATIVES [75] Inventors: LuigiFontanella; Luigi Mariani,

both of Milan, Italy [73] Assignee: Gruppo Lepetit S.p.A., Milan, Italy[22] Filed: May 23, 1973 211 Appl. No.: 363,225

30 Foreign Application Priority Data Primary ExaminerI-Ienry R. JilesAssistant ExaminerR0bert T. Bond Attorney, Agent, or Firm-Theodore Post;C. Kenneth Bjork [57] ABSTRACT 2,4-Benzoxazepine derivatives of formula(I) it (I) wherein R is hydrogen, lower alkyl or benzyl, R and R"independently represent hydrogen, phenyl or substituted phenyl, not morethan one of which is hydrogen and X is hydrogen, halo or lower alkoxy.The fundamental seven-membered benzoxazepine system is prepared byreacting a compound of formula (II) CH- OH wherein R, R, R" and X havethe above meanings, with phosgene or an equivalent carbonylating agent;

The compounds of the invention have hypnotic,

' sedative and myorelaxing activity.

9 Claims, No Drawings 1 ZA-BENZOXAZEPINE DERIVATIVES SUMMARY OF THEINVENTION The present invention. relates to a new class ofpharmacologically active compounds, 2,4-benzoxazepine derivatives offollowing Formula I wherein R is a member of the class consisting ofhydrogen, lower alkyl or benzyl, R and R'f independently representhydrogen, phenyl or substituted phenyl, not more than one of which ishydrogen, and X is hydrogen, halo or lower alkoxy.

As used in the specification and claims, the terms lower alkyl" andlower alkoxy designate groups containing from one, to two, to three, tofour carbon atoms, such as methyl, ethyl, propyl or butyl, and thecorresponding alkoxy groups, substituted phenyl designates phenylsubstituted with halo, lower alkyl orlower alkoxy groups, and halodesignates chloro or bromo.

The process for preparing the fundamental sevenmembered benzoxazepinesystem consists essentially in reacting a compound of formula (II)tin-ml GH--OH wherein R, R, R" and X have the above meanings,- withphosgene or equivalent other carbonylating agent, such as,for instance,c'arbonyl-bis-imidazole, a di-lowe alkyl carbonate orl,3-dioxolan-2-one.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The starting compounds (II) areprepared as described in the examples herein. In a preferred mode forpreparing the fundamental seven-membered benzoxazepine, an amount ofstarting compound (II) is allowed to react with at least two molecularproportions of phosgene in an inert organic solvent, such as benzene,toluene, carbon tetrachloride or trichloroethylene, in the presence of asuitable amount of an alkali metal hydroxide or carbonate acid acceptor.The reaction mixture is stirred for a time varying from about minutes toabout 20 hours at atmospheric pressure within a range of .temperaturevarying from room temperature to the boiling temperature of the solventmedium, or until byproduct chloride of reaction no longer forms. Thefinal product is then recovered, following usual procedures well knownto those skilled in the field of organic chemistry. For instance, thesolvent is evaporated and the residue may be purified by crystallizationfrom a suitable solvent, by chromatography or by fractional distillationunder reduced pressure. The starting-compounds (II) also may be employedas their mineral acid salts; in this case, a suitable amount of a strongbase is required to set free the corresponding starting compound as itsfree base.

Compounds of the general formula (I), wherein R is lower alkyl or benzylalso may be obtained by introducing the appropriate group onto basiccompounds of formula (I), wherein R is hydrogen, through conventionalmethods, for instance by reacting a 4-unsubstituted-2,4-benzoxazepine-3( lH)-one with a suitable lower alkyl or benzylhalide.

Other obvious routes useful for introducing a suitable substituent onthe nitrogen atom of the benzoxazepine ring may be used, and areintended to fall within the scope of this invention.

The following examples further describe the invention and the manner andprocess of making and using it soas to enable any art skilled person tomake and use the same, and set forth the best mode contemplated by theinventors of carrying out the invention.

' EXAMPLE 1 4-Methyl-l -phenyl-4,5-dihydro-2,4-ben2oxazepine- 3(lI-I)-one v j To a mixture of 15.2 g. of 2-methylaminomethylbenzhydroland 12 got finely ground sodium carbonate in ml. of trichloroethylene,asolution of 7.5 g. of phosgene in 30 ml. of trichloroethylene is addeddropwise at 0C. After stirring two hours at 0C. and 2 hours at roomtemperature, 6 g. of sodium carbonate is added thereto and the mixtureis refluxed for 5 hours.

After cooling, the solid salt which forms is filtered off and washedwith diethyl ether. The two organic phases are collected and the titlecompound crystallized on chilling. Yield 5.3 g. M.p. l63-l66C. (fromethanol).

EXAMPLES 2-5 Pursuant to the method described in Example I, thefollowing compounds are prepared, starting with a suitable benzhydroland using about two molecular proportions of phosgene. I 2. 4-Ethyll-phenyl-4,5-dihydro-2,4-benzoxazepine- 3( lH)-one,

from 15 g. of 2-ethylaminomethyl-benzhydrol.Yield 7 g. M.p. llll l3C.(from diisopropyl ether). 3.l-Phenyl-4-propyl-4,5-dihydro-2,4-benzoxazepine- 3( lH)-one,

from 15 g. of 2-propylaminomethyl-benzhydrol.

Yield 8.5 g. M.p. 9698C. (from diisopropylether). 4. 4-Butyll-phenyl-4,5 -dihydro-2,4-benzoxazepine- 3(lH)-one,

from 10 g. of 2-butylaminomethyl-benzhydrol. Yield 6 g. M.p. 54-55C.(from diisopropyl ether). 5. 4-Benzyll -phenyl-4,5-dihydro2,4-benzoxazepine- 3( lH)-one,

y from 8.5 g. of 2-benzylaminomethyl-benzhydrol. Yield 5 g. M.p.l04-l06C. (from diisopropyl ether).

EXAMPLE 6 8-Chloro-1-phenyl-4,5-dihydro-2,4-benzoxazepine- 3( lH)-oneThe title compound is prepared substantially as described in Example 1,substituting 2-aminomethyl-5- chloro-benzhydrol in place of2-methylaminomethylbenzhydrol, and carbonyl-bis-imidazole in place ofphosgene. Yield 41.3%. M.p. 150l52C. (from ethyl acetate).

EXAMPLE 7 8-Chloro-4-methyll -phenyl-4,5-dihydro-2,4-benzoxazepine-3(ll-l )-one Starting with 11 g. of 2-methylaminomethyl-5-chloro-benzhydrol and about two molecular proportions of phosgene, andfollowing the procedure described in Example 1, 8.4 g. of the titlecompound is obtained. M.p. 131l34C. (from methanol).

. EXAMPLE 8 8-Chloro-1-pheny1-4-propyl-4,5-dihydro-2,4-benzoxazepine-3(1l-l)-one The title compound is prepared substantially as described inExample 1, starting with 9.4 g. of 2-propylaminomethyl-S-chloro-benzhydrol and about two molecularproportions of phosgene. Yield 3.5 g. M.p. l03l04C. (from ligroin).

EXAMPLES 9-10 EXAMPLE 1 l4-Butyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine- 3( lH)-one To a mixtureof 8 g. of 2-[a-(butylamino)benzyl]- benzyl alcohol-and 8 g. of sodiumcarbonate in 50 ml. of trichloroethylene, a solution of 3.2 g. ofphosgene in 30 ml. of trichloroethylene is added dropwise at C. Themixture is successively stirred for 1 hour at about C., 1 hour at roomtemperature and 9 hours under reflux. After 4 hours reflux, 4 g. ofsodium carbonate is added to neutralize the hydrogen chloride formedduring the reaction, and refluxing is continued for an additional 5hours. The reaction mixture is then chilled, the inorganic precipitateis separated by filtration, and the solvent is evaporated. The residueis taken up with a mixture of aqueous hydrochloric acid and diethylether. The organic phase is successively washed with water and asolution of sodium hydrogen carbonate and dried over sodium sulfate.After'filtering off the sodium sulfate, the solvent is evaporated,leaving 5 g. of a crude product which is chromatographed through silicagel using benzene containing 3 percent of diethyl ether as the eluent.The title compound is collected and distilled. Yield 1.5 g. B.p. C./0.4mm Hg.

EXAMPLES 12-15 Pursuant to the procedure described in preceding Examplel 1, and employing a proper benzyl alcohol derivative and about twomolecular proportions of phosgene, the following compounds are obtained.

12. 4-Methyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine-3( ll-l)-one,

from 3 g. of 2-[a (methylamino)benzyl]-benzyl alcohol. Yield 1.5 g. M.p.128-13()C. (from diisopropyl ether). 1 13.4-Ethyl-5phenyl-4,5-dihydro-2,4 benzoxazepine- 3(lH)-one,

from 2.2 g. of 2-[a-(ethylamino)benzyl]-benzyl alcohol. Yield 1.1 g.M.p. 162-l63C. (from diisopropyl ether). l4.5-Phenyl-4-propyl-4,5-dihydro-Z,4-benzoxazepine- 3(lH)-one,

from 5.6 g. of 2-[a-(propylamino)benzyll-benzyl alcohol. Yield 3.3 g.M.p. 7072C. (from diisopropyl ether). 15.4-Benzyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine- 3(1H)-one,

from 5.3 g. of 2-[a-(benzylamino)benzyl]-benzyl alcohol. Yield 46 g.M.p. lOll03C. (from diisopropyl ether).

EXAMPLE 16 7-Chloro-4-methyl-5-phenyl-2,4-benzoxazepine- 3(1H).one

The title compound is prepared substantially as described in Example 11, starting with 2.3 g. of 4-chloro- 2 -[a-(methylamino)benzyl]-benzylalcohol. Yield 1.8 g. M.p. 156-l58C. (from light petroleum).

EXAMPLES 17-19 The following compounds are prepared according to themethod described in Example 11 by employing a suitable benzyl alcoholderivative and about two molecular proportions of phosgene.

17. 7-Chloro-4-ethyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine-3( 1H)-one,

from 2.3 g. of 4-chloro-2-[a-(ethylamino)benzyl]- benzyl alcohol. Yield1.1 M.p. 144'l46C. (from diethyl ether). 18.7-Chloro-5-phenyl-4-propyl-4,5-dihydro-2,4-benzoxazepine-3( l H -one,

from 6.3 g. of 4-chloro-2-[a-(propylamino)benzyl]- benzyl alcohol. Yield4.5 g. M.p. 134-137C. (from diethyl ether). l9.7-Chloro-4-butyl-5-phenyl-4,5-dihydro-2 ,4-benzoxazepine-3( l H)-one,

from 3.3 g. of 4-chloro-2-[a-(butylamino)ben2yl]- benzyl alcohol. Yield3.4 g. M.p. 164-l67C. (from diethyl ether).

The following starting compounds of Examples l-5 and 7-10 are preparedsubstantially according to the method described by K. Freter and M.Giitz, Can. Journal of Chemistry 48, 1670, 1970.

Compounds M.p.

* B.p.C./mm Hg.

2-Methylaminomethyl-benzhydrol C./0.6mm Hg.

-Continued 190-200C./0.6mm Hg. l90C./0.6mm Hg. 190195C.l0.6mm Hg.220C.l0.6mm Hg.

Compounds Z-Ethylaminomethyl-benzhydrol 2-Propylaminomethyl-benzhydrol2-Butylaminomethyl-benzhydrol Z-Benzylaminomethyl-benzhydrolS-Chloro-Z-methylaminomethyl benzhydrol 80-82C.S-Chloro-Lpropylaminomethyl benzhydrol 8587C.5-Chloro-2-ethylaminomethyl benzhydrol l95C./0.5mm Hg. 5Chloro-2-butylaminomethyl benzhydrol Sit-60C.

The following starting compound for Example 6 was also preparedsubstantially following the method described by K. Freter and M. G'otzin Can. Journal of Chemistry, 48, 1670, 1970.

M.p. C.

Compound Z-Arninomethyl-S-chloro-benzhydrol Compounds M.p. C.

B.p. C./mm Hg.

4-Chloro-2-[a-(methylamino)benzyl] benzyl alcohol I 1 17-1 18C.4-Chloro-2-[a-(ethylamino)benzyll-benzyl alcohol l90-l95C./0.54-Chloro-2-[a-(propylamino)benzyl1-benzyl alcohol 22S227C. 4Chloro-2-[a-(butylamino)benzyl]-benzyl alcohol The starting compoundsfor Examples 11-15 are prepared in a similar manner as for those ofExamples 16-19 and are advantageously used in the crude state.

2-[a-(butylamino)benzyl]-benzyl alcohol 2-[a-(methylamino)benzyl1-benzylalcohol 2-[a-(ethylamino)benzyl]-benzyl alcohol2-[a-(propylamino)benzyl]-benzyl alcohol2-[a-(benzylamino)benzyl]-benzyl alcohol The compounds of the inventionhave central nervous system activity, characterized by hypnotic,sedative and myorelaxing activity. Representative compounds of theinvention also show an anxiety-relieving effect in rats.

The decrease of the spontaneous activity in mice after intraperitonealadministration of an effective amount of representative compounds ofthis invention was taken as a measure of the sedative effect, whileimpairment of motor coordination and of the righting reflex were relatedto hypnotic properties. The myorelaxing characteristics were evaluatedby considering the body tone, while the anxiety-relieving effect wasmeasured on the basis of the secondary conditioned avoidance response.

In representative experiments, amounts from about to about 100 mg/kgi.p. of compounds of Examples 7, 8, l l and 16 were found to beparticularly active on 6 the mentioned parameters. These favorablepharmacological properties are coupled with a very low toxicity. theLD,-,., values in mice being always higher than 500 mg/kg.

We claim:

1. A benzoxazepine derivative represented by the formula wherein Rrepresents a member of the group consisting of hydrogen, lower alkyl orbenzyl, R and R each independently represents hydrogen, phenyl orsubstituted phenyl, not more than one of which represents hydrogen, Xrepresents a member of the group consisting of hydrogen, halo and loweralkoxy.

2. The compound of claim 1 which is 8-chloro-4-methyl-1-phenyl-4,5-dihydro-2,4-benzoxazepine- 3(lH)-one.

3. The compound of claim 1 which is8-chloro-lphenyl-4-propyl-4,5-dihydro-2,4-benzoxazepine- 3(lH)-one.

4. The compound of claim 1 which is 4-butyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine-3( 1H )-one.

5. The compound of claim 1 which is 7-chloro-4-methyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine- 3(lH)-one.

6. The compound of claim 1 which is 7-chloro-5-phenyl-4-propyl-4,S-dihydro-2,4-benzoxazepine- 3(lH)-one.

7. A process for preparing a benzoxazepine derivative of the formula R Ras CH-O '12" a I ell-1 1E CH-OH wherein R, R, R and X have the abovemeanings with about two molar proportions of a carbonylating agentselected from phosgene and carbonyl-bis-imidazole in the presence of analkali metal hydroxide or carbonate and in an inert organic solvent, ata temperature and 9. The process of claim 6 wherein the carbonylating' Iagent is carbonyl-bis-imidazole.

PC1-1050 I UNHED STAT'IS PATENT @FFECE (IEER'EEHQA'W. W RREYE7WN PatentNo, 3,817,987 Dated June 18, 1974 Inventor(s) Luigi Fontanella and LuigiMariani It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

In the Abstract, Formula (I) should appear as follows:

Column 1, line 10, formula (I) should appear as follows:

Signed and sealed this 2th day of November 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents

2. The compound of claim 1 which is8-chloro-4-methyl-1-phenyl-4,5-dihydro-2,4-benzoxazepine-3(1H)-one. 3.The compound of claim 1 which is8-chloro-1-phenyl-4-propyl-4,5-dihydro-2,4-benzoxazepine-3(1H)-one. 4.The compound of claim 1 which is4-butyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine-3(1H)-one.
 5. Thecompound of claim 1 which is7-chloro-4-methyl-5-phenyl-4,5-dihydro-2,4-benzoxazepine-3(1H)-one. 6.The compound of claim 1 which is7-chloro-5-phenyl-4-propyl-4,5-dihydro-2,4-benzoxazepine-3(1H)-one.
 7. Aprocess for preparing a benzoxazepine derivative of the formula
 8. Theprocess of claim 6 wherein the carbonylating agent is phosgene.
 9. Theprocess of claim 6 wherein the carbonylating agent iscarbonyl-bis-imidazole.